P
US7087785B2ExpiredUtilityPatentIndex 96

Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine and its formamide

Assignee: SEPRACOR INCPriority: Sep 16, 2002Filed: Sep 16, 2003Granted: Aug 8, 2006
Est. expirySep 16, 2022(expired)· nominal 20-yr term from priority
Inventors:JERUSSI THOMAS PFANG QUN KEVINCURRIE MARK G
C07C 2602/10A61P 25/06A61P 25/28C07C 2602/28A61P 25/24A61P 25/14A61P 3/04A61P 25/22A61P 25/20C07B 2200/07A61P 25/00C07C 211/42A61K 31/135A61P 25/08A61P 25/30A61P 25/16
96
PatentIndex Score
28
Cited by
16
References
56
Claims

Abstract

Treatment of CNS disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful.

Claims

exact text as granted — not AI-modified
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula PQ: 
                 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A pharmaceutical composition according to  claim 1 , of formula P or Q: 
                 
 
       or a pharmacuetically acceptable salt thereof. 
     
     
       3. A pharmaceutical composition according to  claim 1  comprising a pharmaceutically acceptable carrier and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine according or a pharmaceutically acceptable salt thereof. 
     
     
       4. A pharmaceutical composition according to  claim 1  comprising a pharmaceutically acceptable carrier and (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine pharmaceutically acceptable salt thereof. 
     
     
       5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of  claims 1  to  4 . 
     
     
       6. A tablet or capsule according to any  claims 1  to  4 . 
     
     
       7. A method for treating CNS disorders in a human, the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of:
 (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (c) a mixture of P and Q; or  
 (d) a pharmaceutically acceptable salt thereof.  
 
     
     
       8. The method according to  claim 7 , wherein the CNS disorder is a mood disorder. 
     
     
       9. The method according to  claim 8 , wherein the mood disorder is depression. 
     
     
       10. The method according to  claim 7 , wherein the CNS disorder is and anxiety-related disorder. 
     
     
       11. The method according to  claim 10 , wherein the anxiety-related disorder is obsessive compulsive disorder. 
     
     
       12. The method according to  claim 7 , wherein the CNS disorder is a disruptive behavior disorder. 
     
     
       13. The method according to  claim 12 , wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit/hyperactivity disorder (ADHD). 
     
     
       14. The method according to  claim 7 , wherein the CNS disorder is a sexual dysfunction. 
     
     
       15. The method according to  claim 7 , wherein the CNS disorder is a substance abuse disorder. 
     
     
       16. The method according to  claim 7 , wherein the CNS disorder is an eating disorder. 
     
     
       17. A method according to  claim 7 , wherein the CNS disorder is premenstrual syndrome disorder. 
     
     
       18. A method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of a compound chosen from:
 (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (c) a mixture of P and Q; and  
 (d) a pharmaceutically acceptable salt thereof.  
 
     
     
       19. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
 (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (c) a mixture of P and Q; or  
 (d) a pharmaceutically acceptable salt thereof, together with  
 (e) a therapeutically effective amount of a D 2  antagonist, or a pharmaceutically acceptable salt thereof.  
 
     
     
       20. The method according to  claim 19 , wherein the D 2  antagonist is olanzapine. 
     
     
       21. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
 (a) (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (b) (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine 
                 
 
 (c) a mixture of P and Q; or  
 (d) a pharmaceutically acceptable salt thereof, together with  
 (e) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof.  
 
     
     
       22. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, the process comprising:
 (a) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide; and  
 (b) hydrolyzing the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthalen-1-yl]formamide with aqueous acid, yielding 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine.  
 
     
     
       23. A compound of formula: 
                 
 
     
     
       24. A compound according to  claim 23 , of formula E: 
                 
 
     
     
       25. A compound according to  claim 23 , of formula F: 
                 
 
     
     
       26. A compound according to  claim 23 , of formula A, B, C, or D: 
                 
 
     
     
       27. (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to  claim 23 . 
     
     
       28. (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to  claim 23 . 
     
     
       29. (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to  claim 23 . 
     
     
       30. (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide according to  claim 23 . 
     
     
       31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of  claims 23  to  30 . 
     
     
       32. A tablet or capsule according to  claim 31 . 
     
     
       33. A method for treating CNS disorders in a human, the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       34. A method according to  claim 33 , the method comprising administering to a person in need of treatment for a CNS disorder, a therapeutically effective amount of:
 (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (e) a mixture of A and B;  
 (f) a mixture of C and D; or  
 (g) a pharmaceutically acceptable salt thereof.  
 
     
     
       35. The method according to  claim 33 , wherein the CNS disorder is a mood disorder. 
     
     
       36. The method according to  claim 35 , wherein the mood disorder is depression. 
     
     
       37. The method according to  claim 33 , wherein the CNS disorder is anxiety-related disorder. 
     
     
       38. The method according to  claim 37 , wherein the anxiety-related disorder is obsessive compulsive disorder. 
     
     
       39. The method according to  claim 33 , wherein the CNS disorder is a disruptive behavior disorder. 
     
     
       40. The method according to  claim 39 , wherein the disruptive behavior disorder is one of attention deficit disorder (ADD) or attention deficit/hyperactivity disorder (ADHD). 
     
     
       41. The method according to  claim 33 , wherein the CNS disorder is a sexual dysfunction. 
     
     
       42. The method according to  claim 33 , wherein the CNS disorder is a substance abuse disorder. 
     
     
       43. The method according to  claim 33 , wherein the CNS disorder is an eating disorder. 
     
     
       44. A method according to  claim 33 , wherein the CNS disorder is premenstrual syndrome disorder. 
     
     
       45. A method for the prophylaxis of migraine in a human, the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       46. A method according to  claim 45 , the method comprising administering to a person at risk or in need of therapy for a migraine, a therapeutically effective amount of a compound chosen from:
 (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (e) a mixture of A and B;  
 (f) a mixture of C and D; or  
 (g) a pharmaceutically acceptable salt thereof.  
 
     
     
       47. A method for treating psychoses in a human, the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       48. A method according to  claim 47 , the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
 (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (e) a mixture of A and B;  
 (f) a mixture of C and D; or  
 (g) a pharmaceutically acceptable salt thereof, together with  
 (h) a therapeutically effective amount of a D 2  antagonist, or a pharmaceutically acceptable salt thereof.  
 
     
     
       49. The method according to  claim 48 , wherein the D 2  antagonist is olanzapine. 
     
     
       50. A method according to  claim 47 , the method comprising administering to a person in need of treatment for a psychoses, a therapeutically effective amount of:
 (a) (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (b) (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (c) (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (d) (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide 
                 
 
 (e) a mixture of A and B;  
 (f) a mixture of C and D; or  
 (g) a pharmaceutically acceptable salt thereof, together with  
 (h) a therapeutically effective amount of an antipsychotic agent, or a pharmaceutically acceptable salt thereof.  
 
     
     
       51. A process for preparing N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone with an excess of formic acid and formamide to provide N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       52. The process according to  claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is of the (S) configuration and the N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1yl]formamide is a 1:1 mixture of(1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       53. The process according to  claim 52 , further comprising separating the (1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       54. The process according to  claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is of the (R) configuration and the N-[4-(3,4-dichloro phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide is a 1:1 mixture of (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       55. The process according to  claim 54 , further comprising separating the (1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and (1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide. 
     
     
       56. The process according to  claim 51 , wherein the 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone is racemic and the process further comprises separating the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide into cis N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide and trans N-[4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydronaphthalen-1-yl]formamide.

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